This invention relates to the field of diagnostic reagents, and in particular to the production of such reagents which contain at least one labile biochemical, e.g., an antibody, nucleotide or enzyme.
For several decades, diagnostic reagents containing labile biochemicals have been employed to provide an assay for a given analyte in order to provide, for example, information for the diagnosis of pathological disorders. See, for example, U.S. Pat. Nos. 3,413,198, Deutsch, issued Nov. 26, 1968; 3,721,725, Briggs et al, issued Mar. 20, 1973; 4,067,775, Wurzburg et al, issued Jan. 10, 1978; and 4,447,527, Monte et al, issued May 8, 1984. In all of these referenced diagnostic reagents, the enzyme was used in a lyophilized condition so that the enzymatic component would not be degraded which would otherwise result in non-uniform and unreliable reagents. The same is true with respect to other degradable components such as, for example, nucleotides and antibodies. Such lyophilized biochemicals were also compounded with each other, e.g., co-enzymes and antibodies, as well as with excipients such as, for example, enzyme stabilizers, bulking agents, buffers, enzyme activators, etc. Heretofore, the components were blended and then formed into larger particles, e.g., tablets, by a variety of means, with the understanding that when diagnostic test tablets are to be employed in automatic clinical analyzers, there is at a minimum a two-fold requirement for the tablets--a uniform concentration of diagnostic ingredients therein and a uniform rate of dissolution from tablet to tablet.
In the conventional blending of small amounts of lyophilized enzyme, e.g., not more than 1% by weight of the total, with a bulking agent, e.g., mannitol, it was discovered that the difference in bulk density between the two constituents was so high that deblending of the constituents could occur after the blending step.
An attempt was made to agglomerate the lyophilized enzyme with the bulking agent, e.g., mannitol, by the fluidized bed agglomeration process, but this proved to be unsuccessful. Because the bulk density of the lyophilized enzyme was so low compared to the mannitol, many difficulties occurred during the fluidization process, not the least of which was that the resultant agglomerate was very fragile, resulting in a breakdown of the agglomerate during further handling. Other difficulties included, for example: loss of the light weight lyophilized enzyme in the filters at the top of agglomeration chamber and loss of product clumped in oversized lumps. Furthermore, the process required a relatively high air temperature to drive the moisture from the binder solution, possibly denaturing the enzyme and/or decomposing other labile components.